Risperidone I is an orally active, potent antipsychotic agent, commercially available in the form of Risperidal.RTM. tablets and oral solution from Janssen Pharmaceutica. ##STR2##
The C.sub.max of risperidone in humans is at about 3 to 9 hours after oral administration, and the serum half-life is about 2 to 22 hours; both of these parameters are highly variable, depending, on the subject's age, liver function, and CYP 2D6 phenotype, as will be discussed below. The major metabolite in human serum is 9-hydroxyrisperidone II (hereinafter, "hydroxyrisperidone"). ##STR3##
The hydroxylation of risperidone to its active metabolite hydroxyrisperidone, is catalyzed in vivo by the hepatic cytochrome P450 enzxme, CYP2D6,an enzyme that is involved in the metabolism of numerous other drugs, including tricyclic antidepressants and selective serotonin reuptake inhibitors. CYP2D6 is polymorphically expressed in the human population and the mutant allele constitutes the recessive trait. Homozygous carriers of the mutation completely lack CYP2D6 and are referred to as poor metabolizers (PM's); persons homozygous for the "normal" allele are extensive metabolizers (EM's); heterozygotes appear to be intermediate in metabolic capacity.
It would be desirable to find a compound that has the advantages of risperidone while providing a more predictable dosage regimen in the patient population and decreasing the chances for drug-drug interactions.
Risperidone is also known to give rise to several side effects, and in particular, to extrapyramidal effects such as tardive dyskinesia. The most frequently, observed adverse reactions include orthostatic hypotension and dizziness, drowsiness, palpitations, weight gain, erectile dysfunction and a significant increase in rashes and rhinitis.
The following adverse events have been reported in risperidone-treated patients:
Psychiatric disorders--insomnia, agitation, anxiety, somnolence, aggressive reaction, increased dream activity, diminished desire, nervousness, depression, apathy, catatonic reaction, euphoria, increased libido, amnesia, emotional lability, nightmares, delerium, withdrawal syndrome, yawning.
Central and Peripheral Nervous system disorders--extrapyramidal symptoms (including tremor, dystonia, hypokinesia, hypertonia, hyperkinesia, oculogyric crisis, ataxia, abnormal gait, involuntary muscle contractions, hyporeflexia, akathisia, increased sleep duration, dysarthria, vertigo, stupor, paraesthesia, confusion, aphasia, cholinergic syndrome, hypoesthesia, tongue paralysis, leg cramps, torticollis, hypotonia, coma, migraine, hyperreflexia and choreoathetosis.
Gastrointestinal system disorders--constipation, nausea dyspepsia, vomiting abdominal pain, increased salivation, anorexia, toothache, reduced salivation, flatulence, diarrhea, increased appetite, stomatitis, melena, dysphagia, hemorrhoids, gastritis, fecal incontinence, eructation, gastroesophageal reflux, gastroenteritis, esophagitis, tongue discoloration, cholelithiasis tongue edema, diverticulitis, gingivitis, discolored feces, GI hemorrhage, hematemesis.
Body as a whole/General disorders--back pain, chest pain, fever, fatigue, edema, rigors, malaise, influenza-like symptoms, pallor, enlarged abdomen, allergic reaction ascites, sarcoidosis, flushing.
Respiratory system--rhinitis, coughing, sinusitis, pharyngitis, dyspnea, hyperventilation, bronchospasm, pneumonia, stridor, asthma, increased sputum, aspiration.
Dermatological--rash, dry skin, seborrhea, increased pigmentation, photosensitivity, increased sweating, acne, decreased sweating, alopecia, hyperkeratosis, pruritus, skin exfoliation, bullous eruption, skin ulceration, aggravated psoriasis, furunculosis, verruca, dermatitis lichenoid, hypertrichosis, genital pruritus, and urticara.
Vision Disorders--abnormal accommodation, xerophthalmia, diplopia, eye pain, blepharitis, photopsia, photophobia, and abnormal lacrimation.
Metabolic and Nutritional Disorders--hyponatremia, weight increase, creatine phosphokinase increase, thirst, weight decrease, diabetes mellitus, decreased serum iron, cachexia, dehydration, hypokalemia, hypoproteinemia, hyperphosphatemia, hypertriglyceridemia, hyperuricemia, and hypoglycemia.
Urinary System Disorders--polyuria/polydipsia, urinary incontinence, hematuria, dysuria, urinary retention, cystitis, and renal insufficiency.
Musculo-Skeletal Disorders--arthralgia, myalgia, arthrosis, synostosis, bursitis, arthritis, and skeletal pain.
Reproductive Disorders--(Female) menorrhagia, orgastic dysfunction, dry vagina, nonpuerperal lactation, amenorrhea, female breast pain, leukorrhea, vaginal hemorrhage, mastitis, dysmenorrhea, femal perineal pain, and intermenstrual bleeding; (Male) erectile dysfunction and ejaculation failure.
Liver and Biliary System Disorders--increased SGOT, increased SGPT, hepatic failure, cholestatic hepatitis, cholecystitis, cholelithiasis, hepatitis and hepatocellular damage.
Endocrine Disorders--gynecomastia, male breast pain, and antidiuretic hormone disorder.
White Cell and Resistance Disorders--leukocytosis, lymphadenopathy, leucopenia, and Pelger-Huet anomaly.
Red Blood Cell Disorders--anemia, hypochromic anemia, and normocytic anemia.
Platelet, Bleeding and Clotting Disorders--epistaxis, purpura, hemorrhage, superficial phlebitis thrombophlebitis, and thrombocytopenia.
Hearing and Vestibular Disorders--tinnitus, hyperacusis, and decreased hearing.
Cardiovascular--tachycardia, orthostatic hypotension, palpitation, hypertension, AV block, myocardial infarction, ventricular tachycardia, angina pectoris, premature atrial contractions, T wave inversions, ventricular extrasystoles, ST depression, myocarditis, angioedema, atrial fibrillation, pulmonary embolism and cardiopulmonary arrest.
Risperidone and hydroxyrisperidone have also been implicated in a prolongation of QT interval, a condition associated with torsades de pointes, a life-threatening arrhythmia.
Accordingly, an anitipsychotic having the efficacy of risperidone, but causing fewer side effects, would be desirable.